The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy

Immunity. 2012 Jun 29;36(6):933-46. doi: 10.1016/j.immuni.2012.03.025.

Abstract

The mitochondrial protein MAVS (also known as IPS-1, VISA, and CARDIF) interacts with RIG-I-like receptors (RLRs) to induce type I interferon (IFN-I). NLRX1 is a mitochondrial nucleotide-binding, leucine-rich repeats (NLR)-containing protein that attenuates MAVS-RLR signaling. Using Nlrx1(-/-) cells, we confirmed that NLRX1 attenuated IFN-I production, but additionally promoted autophagy during viral infection. This dual function of NLRX1 paralleled the previously described functions of the autophagy-related proteins Atg5-Atg12, but NLRX1 did not associate with Atg5-Atg12. High-throughput quantitative mass spectrometry and endogenous protein-protein interaction revealed an NLRX1-interacting partner, mitochondrial Tu translation elongation factor (TUFM). TUFM interacted with Atg5-Atg12 and Atg16L1 and has similar functions as NLRX1 by inhibiting RLR-induced IFN-I but promoting autophagy. In the absence of NLRX1, increased IFN-I and decreased autophagy provide an advantage for host defense against vesicular stomatitis virus. This study establishes a link between an NLR protein and the viral-induced autophagic machinery via an intermediary partner, TUFM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology
  • Amino Acid Sequence
  • Animals
  • Autophagy / physiology*
  • Autophagy-Related Protein 12
  • Autophagy-Related Protein 5
  • Autophagy-Related Proteins
  • Carrier Proteins / physiology
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / physiology
  • Fibroblasts / metabolism
  • Gene Expression Regulation / immunology
  • HEK293 Cells
  • Humans
  • Interferon Type I / biosynthesis*
  • Interferon Type I / genetics
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / immunology
  • Mice
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / physiology
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / deficiency
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / physiology*
  • Molecular Sequence Data
  • Multiprotein Complexes / physiology
  • Peptide Elongation Factor Tu / chemistry
  • Peptide Elongation Factor Tu / physiology*
  • Protein Interaction Mapping
  • Proteins / physiology
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / physiology
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Specific Pathogen-Free Organisms
  • Vesiculovirus / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Atg12 protein, mouse
  • Atg16l1 protein, mouse
  • Atg5 protein, mouse
  • Autophagy-Related Protein 12
  • Autophagy-Related Protein 5
  • Autophagy-Related Proteins
  • Carrier Proteins
  • Cytokines
  • Interferon Type I
  • MAVS protein, human
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Multiprotein Complexes
  • NLRX1 protein, human
  • NLRX1 protein, mouse
  • Proteins
  • Recombinant Fusion Proteins
  • TUFM protein, human
  • Ddx58 protein, mouse
  • Peptide Elongation Factor Tu
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases